Autoimmune Blistering Diseases in Children

Autoimmune Blistering Diseases in Children
Irene Lara-Corrales, MD, MSc, and Elena Pope, MD, MSc
Autoimmune blistering disorders comprise a series of conditions in which autoantibodies
target components of the skin and mucous membranes, leading to blister and bullae
formation. Most conditions in the spectrum of autoimmune blistering disorders are uncommonly seen in the pediatric population, even the most common ones, such as chronic
bullous disease of childhood and dermatitis herpetiformis; however, they often come into
the differential diagnosis of other more common pediatric entities. In addition, prompt
recognition and treatment avoids unnecessary morbidity and improves ultimate outcome.
Semin Cutan Med Surg 29:85-91 © 2010 Published by Elsevier Inc.
he incidence and prevalence of childhood autoimmune
blistering disorders (ABD) is unknown because most of
the existing literature consisting of case reports and case series. Blister formation, the clinical hallmark of these conditions,
is caused by the interaction between structures essential for the
integrity of the skin (desmosomes, hemidesmosomes, anchoring fibrils, etc.) and autoantibodies, leading to cleavage of the
skin at various levels. Clinical diagnosis alone is difficult and
requires histologic and immunopathological corroboration.
Other conditions, such as bullous impetigo, herpetic infections, bullous erythema multiforme, Stevens–Johnson syndrome, inherited forms of porphyria, and congenital blistering disorders (epidermolysis bullosa), should be considered
in the differential diagnosis. Genital involvement should be
differentiated from sexual abuse, bullous lichen sclerosus,
and bullous fixed drug eruption.
The most common ABDs in childhood are chronic bullous
disease of childhood and dermatitis herpetiformis (DH). Less
frequently seen entities are pemphigus, epidermolysis bullosa acquisita (EBA), herpes (pemphigoid) gestationis (HG),
cicatricial pemphigoid (CP), bullous pemphigoid (BP), and
bullous systemic lupus erythematosus.
Chronic Bullous
Disease of Childhood
Chronic bullous disease of childhood (CBDC), also referred
to as linear immunoglobulin A (IgA) disease of childhood, is
Department of Pediatrics, University of Toronto, Hospital for Sick Children,
Toronto, Canada.
Address reprint requests to Irene Lara-Corrales, MD, MSc, or Elena Pope,
MD, MSc, Hospital for Sick Children, 555 University Avenue, Toronto,
ON, M5G 1X8, Canada. E-mail: [email protected] or
[email protected]
1085-5629/10/$-see front matter © 2010 Published by Elsevier Inc.
an acquired autoimmune subepidermal blistering disorder
that is characterized by the deposition of a linear band of IgA
along the dermal– epidermal junction. CBDC is thought to be
the result of a humoral response to a normal constituent of the
epidermal basement membrane zone (BMZ). Although the
target antigen is known to be present in all human stratified
squamous epithelia, it has not yet been defined with certainty. There may be a genetic susceptibility to CBDC with an
increased incidence of HLA-B8, HLA-DR3, and HLADQW2.1 However, the molecular basis of CBDC has not yet
been clearly determined. This condition is seen in all ethnic
groups and seems to be more common in developing countries. In the United Kingdom, its incidence has been estimated to be 1 in 500,000 children.2
The age of onset is typically before 5 years of age. Both skin
and mucous membranes are affected, and typically the condition is preceded by a short nonspecific prodromal illness.
The abrupt onset of tense vesicles on normal-looking skin or
occasionally on urticated plaques is characteristic of the disease (Fig. 1). Skin findings may be accompanied by systemic
symptoms, such as fever or anorexia. Blisters may be localized or widespread, with most common locations being face,
extremities, genital area, and trunk.3 A pathognomonic feature is “string of pearls” rosettes or “cluster of jewels” appearance created by the development of new blisters at the margin
of the old ones. Lesions may present with central clearing and
have a polycyclic appearance. Mild pruritus has been described. Bullae resolve with transient pigmentary changes,
and do not generally leave permanent scarring. Mucous
membranes may be affected in up to 76% of patients.4
On histologic examination, subepidermal bullae are seen,
and an inflammatory infiltrate with neutrophils or eosinophils can be found. Histology of fresh lesions on its own is not
diagnostic and cannot distinguish CBDC from other autoimmune vesiculobullous disorders. The diagnosis relies on the
I. Lara-Corrales and E. Pope
Figure 1 Patient with CBDC.
immunohistochemical demonstration of a linear band of IgA
along the dermal-epidermal junction that may be associated
with weaker bands of IgG, IgM, or C3. The biopsy should be
taken from peri-lesional skin. False-negative results may be
seen early in the disease and may require a repeat biopsy for
histologic confirmation.
Most cases of CBDC spontaneously resolve within 5 years
of onset; few may progress through puberty and into adulthood. There is no correlation between the severity of blistering and disease chronicity.
Despite its good prognosis, most children are offered treatment to decrease the disease severity and shorten its duration. The most frequent medication is dapsone, starting at 0.5
to 1 mg/kg of body weight per day and increasing up to 2
mg/kg depending on the response. A normal glucose-6-phosphate-dehydrogenase level is a prerequisite of treatment initiation (to avoid hemolytic anemia) and baseline and
monthly blood investigations are required for treatment
monitoring. Most widespread cases may require additional
treatment with oral prednisolone at 1 mg/kg/d for 1 to 3
weeks, tapered over 3 to 6 weeks, allowing disease control
until dapsone’s antiinflammatory effects occur. Topical steroids may be useful either as additional therapy for symptom
control or single therapy for mild cases. Other systemic therapeutic options are sulfamethoxypyridazine and sulfapyridine.
as intensely pruritic vesicles, erythematous papules, and urticarial plaques. Intact vesicles are rarely seen as the result of
intense pruritus; most lesions are small excoriations/crusts.
Scarring rarely occurs in the absence of suprainfection. The
symmetry of the body involvement is very characteristic, typically affecting the extensor surfaces of the limbs, buttocks,
shoulders, nape of neck and scalp (Fig. 2). Mucous membrane involvement is rarely encountered.
Gluten-sensitive enteropathy (subclinical or clinical) is
present in almost all children with DH, but only a small
fraction of them (10%) have a diagnosis of celiac disease at
the time of the DH presentation.8 Most children have minimal or no symptoms of gluten-sensitive enteropathy. In up to
40% of children with DH there is a history of chronic or
relapsing diarrhea before the diagnosis of DH.9
To avoid overdiagnosis, pathologic confirmation of the
disease is mandatory. Classically, a subepidermal blister with
neutrophilic (and occasionally eosinophilic) microabscesses
within the dermal papillae is seen and fibrin deposition is
common. The pathognomonic diagnostic feature is the presence of a granular deposition of IgA within the dermal papillae, occasionally accompanied by C3, on direct immunofluorescence examination of perilesional skin. The principal
target antigen is epidermal transglutaminase.10 Similarly, a
gastrointestinal work-up for celiac disease is necessary, particularly before a gluten free diet is recommended, as this will
quickly interfere with the endoscopy findings.
With clinical suspicion of DH, it is also useful to measure
the circulating IgA autoantibody to tissue transglutaminase
(target antigen in celiac disease) because its titer reflects the
degree of abnormality in the jejunal mucosa5 and can be used
to monitor response to treatment or disease recurrence. Testing
for IgA titers should be simultaneously performed because IgA
deficiency, commonly seen in general popualtion, leads to a
Dermatitis Herpetiformis
Dermatitis herpetiformis (DH) is a chronic ABD. Although it
thought to be one of the most common ABD in childhood,5,6
its exact prevalence remains unknown. DH has an equal gender presentation, is seen more commonly in Europe than in
North America, and is unusual in patients of African and
Asian background. Age at presentation varies, depending on
the studies, ranging from 2 to 7 years,7 to a mean of 14 years.6
Cutaneous lesions of DH in childhood classically present
Figure 2 Patient with DH.
Autoimmune blistering diseases in children
false-negative serology testing. The determination of anti-endomysial/antigliadin and other antibodies have been shown to
be highly sensitive for celiac disease in children11 but might be
negative in up to 40% of cases of adult DH.12 Thus, their value in
diagnosing DH in children remains to be determined.
The combination of a gluten-free diet and dapsone are
used for an effective treatment. A gluten-free diet alone may
be sufficient because it reverses the intestinal abnormality in
all cases and may lead to the disappearance of skin lesions in
up to 82% of patients within 1 to 3 months.9 Dapsone is also
an effective treatment for the eruption but does not reverse
the gastrointestinal abnormalities. The standard initial dose
of dapsone in childhood is 0.5 to 2 mg/kg/d.13 Once control
of the disease has been obtained, the dosage of dapsone
should be tapered. If the patient continues on a gluten-free
diet, it may be possible to stop dapsone completely and
quickly. Other treatment modalities, such as sulfapyridine,
sulfamethoxypyridazine and systemic steroids can be considered. Super potent topical corticosteroids for short periods
can be used as a dapsone-sparing agent.
The long-term prognosis for childhood DH remains uncertain. Long remissions are possible, but relapses are common typically as the result of poor adherence to the glutenfree diet, which is required lifelong.
Pemphigus refers to a group of autoimmune vesiculobullous
diseases that are characterized by the presence of antidesmosomal antibodies that lead to acantholysis and intraepidermal
blister formation. These conditions can be classified into 2
main groups: the suprabasal type that includes pemphigus
vulgaris (PV) and pemphigus vegetans and the superficial
type, which includes pemphigus foliaceus (PF) and pemphigus erythematosus. The first group is generally associated
with mucous membrane involvement while in the second 1
mucous membrane involvement is not a major feature.
Pemphigus is rarely seen in childhood, with a mean age of
12 years at presentation.14 Several environmental factors,
such as medications15 and acantholytic substances16 superimposed on a genetic predisposition, may play a role in the
onset of the disease. In children the most common form is
PV, followed by PF. Other types, such as pemphigus vegetans7 and erythematosus17 are very rare.
Pemphigus Vulgaris
The blisters seen in PV are typically very flaccid and quickly
rupture, leaving painful and persistent erosions and crusts in
the skin. Nikolsky’s sign is positive in this condition. Because
blisters in PV are superficial, scarring is unusual.
Mucous membrane involvement, particularly of the oral
mucosa, is frequent, severe, and may be the initial presenting
feature. Other mucosal membranes are less frequently affected. PV should be in the differential diagnosis of mucosal
blistering in both adults and children.
Antibodies against one of the desmosomal proteins, desmoglein 1 and 3, seem to play the central role in the patho-
genesis of both the superficial and suprabasal forms of pemphigus,18 but other autoantibodies such as antiacetylcholine
receptor antibodies also seem to be of importance.19 The
histologic characteristics of PV are acantholysis, with floating
keratinocytes in the suprabasal cleavage plane, with the basal
keratinocytes still attached to the epidermal basement membrane. A dermal infiltrate of lymphocytes, neutrophils and
eosinophils is also typically seen.
With direct immunofluorescence of involved or perilesional skin, a deposition of IgG surrounding keratinocytes is
seen and gives a “chicken wire” or “crazy paving” pattern.
This is seen in both suprabasal and superficial forms of pemphigus. Repeat biopsies may sometimes be necessary for a
diagnosis.18 Indirect immunofluorescence of the serum of
patients with PV may show the circulating antibody; its titers
correlate with clinical severity and can be used to monitor
response to treatment.
Systemic corticosteroid therapy is the mainstay of treatment for PV in childhood. Prednisolone is used as a first line
agent in doses of 1 to 2 mg/kg/d. Most patients require a steroidsparing agent, such as dapsone,20 azathioprine,7 methotrexate,7
cyclophosphamide,14 or hydroxychloroquine.21 Potent topical
or intralesional corticosteroid can be used for isolated recalcitrant foci of persistent blistering. Children with PV typically
have a better prognosis than adults.14
Pemphigus Foliaceus
PF is also referred to as superficial pemphigus, and it is
rarely seen in children. The desmosomal protein, desmoglein-1, is the target antigen in this condition. Two different forms of PF have been recognized: an endemic form,
Fogo selvagem, and a nonendemic. The etiology of the
nonendemic form has not been identified, but in adults,
certain drugs, like penicillamine, nifedipine, captopril,
and quinolones, among others, have been associated with
the disease.22 The nonendemic form presents at an average
age of 7.7 years,21 with superficial erosions on the scalp
and the face. The erosions are the result of the thin, fragile
blister roof that sloughs off easily as the tension of the
blister fluid increases. The superficial erosions resemble
an exfoliative dermatitis and are commonly mistaken for
impetigo.7 Occasionally, lesions may take arcuate, circinate or polycyclic patterns, which can make diagnosis
even more difficult.21
In PF, the degree of acantholysis may be subtle. Acantholysis is seen in the upper epidermis and may result in a subcorneal separation. A mild dermal lymphocytic infiltrate may
be found, frequently with eosinophils. Direct immunofluorescence does show the deposition of IgG around keratinocytes. PF in children has a good prognosis. Treatment is the
same as for PV, but because of its milder nature, PF may just
require topical corticosteroid therapy.
Paraneoplastic Pemphigus
Paraneoplastic pemphigus has been associated with B-cell
lymphoproliferative neoplasms, and it is extremely rare in
children. It is characterized by severe oral mucositis and lichenoid lesions on the skin, and in pediatrics it has been
recognized as a presenting sign of occult Castleman’s disease.23,24 The most constant diagnostic marker has been identified to be the serum autoantibodies against plakin proteins.23 Prognosis is extremely guarded with high mortality
secondary to bronchiolitis obliterans and sepsis.23
Epidermolysis Bullosa Acquisita
Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal immunobullous disorder that occurs infrequently
rare in childhood. No gender or racial predilection has been
reported for childhood EBA. An increased incidence of HLADR2 has been identified in some patients with EBA, suggesting a genetic susceptibility.25
Clinical features of EBA are variable,26 and clinical distinction alone may not be possible. Age of presentation can be at
anytime during childhood, starting with infancy.27 Three
clinical phenotypes have been recognized. The first is a classic noninflammatory mechano-bullous type that resembles
the congenital form of dystrophic EB: skin fragility, with
blisters and erosions seen at sites of trauma, particularly over
acral bony prominences; milia formation; atrophic scars with
pigmentary changes; and nail dystrophy. The second type is
an inflammatory type that imitates CBDC, presenting with
pruritic, tense bullae, on normal, erythematous or urticarial
skin. Occasional hemorrhagic lesions may occur forming
crusts and resolving with pigmentary changes. Severe mucous membrane involvement can be seen.28,29 The third clinical variant of EBA resembles CP, presenting with predominantly mucous membrane involvement and a pronounced
tendency to scar. The severe involvement of mucous membranes in children may lead to a variety of complications:
malnutrition, symblepharon of the conjunctivae which may
progress to blindness,30 and stenosis of the esophagus, urethra or genital tract. Although all types are seen, the inflammatory form is more common in the pediatric population, as
is the mucosal involvement. Children also tend to respond
faster to systemic therapy.31
The target of the autoantiboides in EBA is type VII collagen
that is part of the anchoring fibrils of the epidermal basement
membrane. Histologic examination of fresh lesions reveals subepidermal bullae and a predominantly neutrophilic inflammatory infiltrate admixed with eosinophils. With direct immunofluorescence examination of perilesional skin, linear depositions
of IgG and C3 along the BMZ are detected, but sometimes weak
staining for IgA and IgM are also seen. In few cases, IgA may be
the predominant immunoreactant.30 In EBA, indirect immunofluorescence is usually positive, the circulating antibody labels
the dermal side of the bulla in salt-split normal human skin,32
and direct immunoelectron microscopy reveals IgG deposits
under the lamina densa.
Early-onset EBA needs to be differentiated from inherited
dystrophic epidermolysis bullosa. Birth presentation and results of direct immunofluorescence (positive for EBA, negative for dystrophic epidermolysis bullosa) help to differenti-
I. Lara-Corrales and E. Pope
ate between these 2 conditions: however, genetic testing
might be required to make a more definitive demarcation.33
Combination therapy with prednisolone 1 mg kg⫺1 d⫺1
and dapsone 2 mg kg⫺1 d⫺1 is effective in controlling the
disease manifestation.34 Patients usually respond quickly to
treatment, within weeks, and then prednisolone can be tapered off. Alternative therapies that have been reported include sulfapyridine, a combination of nicotinamide and
erythromycin, and for localized cases, superpotent topical
steroids. Long-term prognosis for EBA in children is much
better than its adult counterpart. Children with EBA generally undergo remission within 1 to 4 years, although some
might take longer to resolve.
Herpes (Pemphigoid) Gestationis
and Neonatal Pemphigus
Herpes (pemphigoid) gestationis (HG) is a rare autoimmune
disease that presents during pregnancy or in the postpartum
period. It is seen in about 1 of 50,000 pregnancies. Aproximately 2% to 10% of the neonates born to women with HG
will be affected35,36 because of the passive transplacental
transfer of IgG antibodies from the mother before delivery.37
Antibodies usually target BP180 and occasionally BP230.38
As the antibody titers decrease, the clinical manifestations in
the infant disappear typically within 2 weeks to 3 months.39
Patients characteristically present with intensely pruritic urticarial plaques with tense bullae.
Histologic examination of the lesions shows subepidermal
edema and blistering that is associated with a moderate dermal eosinophilic infiltrate. Direct immunofluorescence of
perilesional skin generally shows a linear deposition of C3 in
the epidermal basement membrane, with a linear deposition
of IgG in up to 25% to 50% of cases.40,41 Indirect immunofluorescence examination may show circulating IgG antibodies confined to the epidermal side of the salt-split skin.
Although specific treatment is not needed, moderately potent topical corticosteroids may help patients with a significant inflammatory component. The prognosis for infants
with cutaneous involvement is generally good. All infants
born to women with HG are at risk of being small for gestational age and have a tendency to prematurity.
Cicatricial Pemphigoid
Cicatricial pemphigoid (CP) is also referred to as benign mucous membrane pemphigoid and is an extremely rare condition in childhood. There are clinical, histologic, and immunopathological overlaps between CP and other autoimmune
subepidermal blistering disorders. It has been proposed that
CP in children is an unusual and more severe form of
CBDC.42 Because of its rarity in childhood, diagnosis may be
It commonly presents as a generalized eruption that involves the face, trunk, and limbs and is characterized by
urticarial or annular, polycyclic, or target-like lesions. The
Cutaneous lesions
● Tense vesicles on
normal/urticarial patches
● “String of pearls”
Most common
Mucosal involvement
Genital area
● Subepidermal blisters
● Inflammatory infiltrate
with Eos and PMN
● Linear IgA along dermal
epidermal junction
First-line treatment
● Dapsone
● polymorphic (small
vesicles, erythematous
papules and urticarial
plaques)— erosions
● Crusts
● Extensor surfaces of the
● Buttocks
● Shoulders
● Nape of neck
● Scalp
● Subepidermal blisters with
microabscesses within
dermal papillae
● Fibrin deposition
● Granular deposits of IgA
within dermal papillae
● Dapsone
● Gluten free-diet
● Flaccid blisters
● Painful/persistent
erosions and crusts
Upper torso
Oral mucosa Only
Frequent and severe (oral
mucosa mostly)
● Acantholysis
● Dermal infiltrate
(lymph, PMN, Eos)
● IgG deposition around
keratinocytes “chicken
wire” or “crazy paving”
● Systemic
● exfoliative
● arcuate, circinate
or polycyclic
● Head and neck
● Large, tense blisters
that may be
Autoimmune blistering diseases in children
Table 1 Comparison of the Most Common Pediatric ABDs
● Acral (palms and soles)
● Flexural areas (inner
thighs, forearms, axillae,
lower abdomen, and
ⴞ to ⴙⴙⴙ
● Subtle acantholysis
● Subcorneal
● Dermal lymph
infiltrate ⴞ Eos
● Deposition of IgG
● Subepidermal blisters
with eosinophilia
● Systemic or topical
● Systemic corticosteroids
● Linear deposits of IgG
or C3 at basement
membrane zone
ABD, autoimmune blistering disorders; BP, bullous pemphigoid; CBDC, chronic bullous disease of childhood; DH, dermatitis herpetiformis; PF, pemphigus foliaceus; PV, pemphigus vulgaris; Eos,
I. Lara-Corrales and E. Pope
predominant clinical feature is the severe involvement of mucous membranes, leading to various degrees of scarring.
Multiple target antigens for CP have been described, such
as BP180,35 laminin 5, type VII collagen, beta 4 subunit of the
␣6␤4 integrin,44 accounting for its clinical heterogenicity.
Direct immunofluorescence may reveal IgA and/or IgG deposited in a linear pattern at the dermal– epidermal junction.
Indirect immunofluorescence detects circulating antibodies
against epithelial basement membrane constituents in about
50% of cases.45 Immunoelectron microscopy shows immunoreactants on the lower part of the lamina Lucida or on the
lamina densa, correlating with the deposition of IgG to the
target antigens.
Treatment consists of either systemic corticosteroids, dapsone or sulfapyridine.42 Topical treatment with steroids may
provide relief of symptoms. Complete remission is possible
with very few cases extending into adulthood.
Bullous Pemphigoid
Bullous pemphigoid (BP) rarely presents in children. Diagnostic criteria have been proposed to facilitate early recognition of childhood BP: (1) age 18 years and younger; (2) clinical appearance of tense blisters; (3) subepidermal blisters
with eosinophilia; and (4) linear deposits of IgG or C3 at the
epidermal BMZ on direct immunofluorescence of perilesional skin, or circulating IgG anti-BMZ autoantibodies on
indirect immunofluorescence using patient serum.46
Clinically, BP presents with tense bullae, sometimes hemorrhagic, arising from normal or inflamed skin. Urticarial
plaques are common, seen in annular or polycyclic patterns.
Folds (particularly groin and axilla), abdomen and inner
thigh involvement are very common. Palmar and plantar involvement is characteristic of infantile-onset BP and can be
seen in up to 79% of affected infants versus 17% of older
children.47,48 Facial involvement is more common in childhood BP and can easily be misdiagnosed as impetigo. Childhood characteristics of the disease are frequent mucous
membrane involvement, acral distribution, and no clear link
to malignancies.
The targets of the autoantibodies in BP are BP230 and/or
BP180, 2 hemidesmosome-associated proteins. Histology of
BP shows subepidermal blistering with an intact overlying
epidermis and no necrosis. Inflammatory infiltrate is mostly
composed of eosinophils, with some neutrophils and lymphocytes. Direct immunofluorescence may reveal a linear
deposition of IgG and C3, and less frequently, IgM and IgA
may be found.49 Indirect immunofluorescence may demonstrate a circulating antibody which is directed against the
epidermal side of salt-split normal human skin, but occasionally dermal binding may be observed, despite Western immunoblotting revealing an epidermal location for the target
antigens.50 Immunoelectron microscopy shows deposition of
autoantibody in the upper lamina Lucida.
The treatment of choice for BP is systemic corticosteroids,
starting with a dose of prednisolone of 1 to 2 mg/kg/d.51
Other treatment modalities have been used, like dapsone or
sulfapyridine or a combination of erythromycin and nicotin-
amide.50 Prognosis for children with BP is good, with most
cases lasting for 1 year or less.
Bullous Systemic
Lupus Erythematosus
Bullous systemic lupus erythematosus, defined as an ABD
presenting in an individual that meets criteria for the diagnosis of systemic lupus erythematosus, is rarely seen in children. Sun-exposed areas are more commonly involved with a
chronic, widespread, itchy, nonscarring bullous eruption,
with tense blisters arising on normal or urticated skin. Rarely,
mucous membrane involvement may be seen.
Although type VII collagen has been described as the target
antigen in this condition, autoantibodies are produced to a
variety of other molecules that may be involved in dermal–
epidermal adhesion, such as BP antigen 1 (BP230), laminin 5,
and laminin 6.52
Histologically, bullous systemic lupus erythematosus presents with subepidermal blistering with a predominantly
neutrophilic infiltrate within the upper dermis. Direct immunofluorescence of lesional skin shows IgG and complement
deposition along the epidermal basement membrane, with
sporadic weaker staining with IgA and/or IgM. Indirect immunofluorescence examination on salt-split skin usually
shows antibody localization to the dermal side. Ultrastructural examination shows immune deposits on or beneath the
lamina densa of the dermal– epidermal junction.
The treatment of choice for bullous systemic lupus erythematosus is dapsone, and the blistering tendency usually
responds quickly. Although the prognosis of the blistering
eruption is good, the ultimate outcome depends on the degree of systemic involvement.
Distinguishing between the different ABD in children is a
difficult and challenging task. Table 1 presents characteristics
of the most common ABD disorders in pediatrics. Knowledge
of the various clinical characteristics of these disorders will
aid in their diagnosis; however, histology and immunofluorescence studies are required to differentiate them.
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